N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for?

Martínez-Banaclocha, Marcos

doi:10.1016/j.mehy.2012.03.021

Cited by 38 publications

(35 citation statements)

References 54 publications

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“…The therapeutic goal of NAC in PD is to normalize neuronal GSH levels and thereby restore neuronal antioxidant capacity [13,14]. Here we employed a strategy in which we first used an animal model to identify the CSF concentration of the drug required to have a biological effect in neurons, and then enrolled human subjects to identify the dose required to achieve this drug concentration in human CSF.…”

Section: Discussionmentioning

confidence: 99%

“…Cysteine availability is normally the rate-liming factor in GSH synthesis [12], and consequently NAC can be used to promote GSH synthesis under conditions in which GSH consumption exceeds supply. NAC is currently approved by the US Food and Drug Administration for the treatment of acetaminophen toxicity and contrast nephropathy, and it has been identified as promising agent for treatment of PD [3,[13][14][15]. There is also a growing interest in the use of NAC to treat other neurological and psychiatric disorders in which oxidative stress has been implicated, including adrenoleukodystrophy, Alzheimer disease, schizophrenia, and compulsive disorders [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

et al. 2016

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N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson's disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 μM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

et al. 2016

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“…NAC is already FDA approved for both short term and long-term indications [20], and given the known associations between GSH and PD pathogenesis, several authors have identified NAC as a promising neuroprotective therapy in PD [6,9,21,22]. Prior studies using antioxidants to slow progression of PD have shown no clinical benefit [23].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson's disease

Katz

Won

Park

et al. 2015

Parkinsonism & Related Disorders

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a b s t r a c tIntroduction: Depletion of neuronal glutathione may contribute to the pathogenesis of Parkinson's disease (PD). N-acetylcysteine (NAC) can restore neuronal glutathione levels, but it has not been established whether NAC can cross the bloodebrain barrier in humans. Methods: Twelve patients with PD were given oral NAC twice daily for 2 days. Three doses were compared: 7 mg/kg, 35 mg/kg, and 70 mg/kg. NAC, cysteine, and glutathione were measured in the cerebrospinal fluid (CSF) at baseline and 90 min after the last dose. Cognitive and motor functions were assessed pre-and post-NAC administration using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale part III motor subscore (UPDRS-III). Results: Oral NAC produced a dose-dependent increase in CSF NAC concentrations (p < 0.001), with the highest dose producing a CSF concentration of 9.26 ± 1.62 mM. There were no significant adverse events.NAC had no acute effect on motor or cognitive function. Conclusion: Orally administered NAC produces biologically relevant CSF NAC concentrations at doses that are well tolerated. The findings support the feasibility of NAC as a potential disease-modifying therapy for PD.

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“…Treating EAAT3 KO mice with NAC rescues dopaminergic cells, as well as motor function (Berman et al, 2011). As might be expected, NAC could potentially be a treatment in PD patients (Martinez-Banaclocha, 2012), and at the time of writing, clinical trials for the use of NAC as PD treatment are currently posted (https://clinicaltrials.gov/ct2/show/NCT01470027, https://clinicaltrials.gov/ct2/show/NCT02212678). While dysregulation of EAAT3 in Parkinson’s disease has not, to the best of our knowledge, been reported, development of drugs that modulate EAAT3 expression and/or function may also be beneficial treatments through a similar mechanism.…”

Section: Functionmentioning

confidence: 98%

The importance of the excitatory amino acid transporter 3 (EAAT3)

Bjørn‐Yoshimoto

Underhill

2016

Neurochemistry International

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The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.

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N-acetyl-cysteine in the treatment of Parkinson’s disease. What are we waiting for?

Cited by 38 publications

References 54 publications

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson's disease

The importance of the excitatory amino acid transporter 3 (EAAT3)

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